rs143124288

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):​c.775G>A​(p.Gly259Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G259D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 3)
Exomes 𝑓: 0.0000099 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

14
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.85
Variant links:
Genes affected
CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000071.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-43063952-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2736999.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 21-43063953-C-T is Pathogenic according to our data. Variant chr21-43063953-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 538698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43063953-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CBSNM_000071.3 linkuse as main transcriptc.775G>A p.Gly259Ser missense_variant 9/17 ENST00000398165.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CBSENST00000398165.8 linkuse as main transcriptc.775G>A p.Gly259Ser missense_variant 9/171 NM_000071.3 P1P35520-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
8270
Hom.:
0
Cov.:
3
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000803
AC:
2
AN:
248994
Hom.:
0
AF XY:
0.00000742
AC XY:
1
AN XY:
134798
show subpopulations
Gnomad AFR exome
AF:
0.0000627
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000991
AC:
2
AN:
201886
Hom.:
0
Cov.:
0
AF XY:
0.00000932
AC XY:
1
AN XY:
107256
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000462
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000955
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
8270
Hom.:
0
Cov.:
3
AF XY:
0.00
AC XY:
0
AN XY:
3722
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Classic homocystinuria Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 27, 2024- -
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2023This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 259 of the CBS protein (p.Gly259Ser). This variant is present in population databases (rs143124288, gnomAD 0.005%). This missense change has been observed in individual(s) with homocystinuria (PMID: 24211323; Invitae). ClinVar contains an entry for this variant (Variation ID: 538698). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 22267502). For these reasons, this variant has been classified as Pathogenic. -
Homocystinuria Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 14, 2023Variant summary: CBS c.775G>A (p.Gly259Ser) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248994 control chromosomes. c.775G>A has been reported in the literature in multiple individuals affected with Homocystinuria (example, Karaca_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting a non-functional outcome in a yeast based functional assay, however, primary data supporting this outcome are not presented (Mayfield_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;D;D;D
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.88
.;.;.;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
4.2
H;H;H;H
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-6.0
D;D;D;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.99
MVP
0.95
MPC
1.1
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.99
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143124288; hg19: chr21-44484063; API